Dexmedetomidine Supplemented Analgesia and Incidence of Postoperative Delirium

Sponsor

Peking University First Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT03012984

Collaborator

Affiliated Hospital of Hebei University (Other), Qingdao Municipal Hospital (Other), The Second Affiliated Hospital of Air Force Medical University (Other), Peking University International Hospital (Other), Guizhou Provincial People's Hospital (Other), The Third Xiangya Hospital of Central South University (Other), Shanxi Provincial Cancer Hospital (Other), Tianjin Hospital of ITCWM-Nankai Hospital (Other), Zhongda Hospital Southeast University (Other), Chongqing University Fuling Hospital (Other)

1,500

Enrollment

Locations

Arms

63.8

Anticipated Duration (Months)

136.4

Patients Per Site

2.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Delirium is a frequently occurred cerebral complication in elderly patients after surgery, and its occurrence is associated with worse outcomes. Sleep disturbances is considered to be one of the most important risk factors of postoperative delirium. Previous studies showed that, for elderly patients admitted to the ICU after surgery, low-dose dexmedetomidine infusion improved the quality of sleep and decreased the incidence of delirium. The investigators hypothesize that, for elderly patients after cancer surgery, dexmedetomidine supplemented analgesia can also decrease the incidence of delirium, possibly by improving sleep quality. The purpose of this multicenter, randomized controlled trial is to investigate the impact of dexmedetomidine supplemented analgesia on the incidence of delirium in elderly patients after cancer surgery.

Condition or Disease	Intervention/Treatment	Phase
Elderly Surgery Analgesia Dexmedetomidine Complication, Postoperative Delirium	Drug: Dexmedetomidine supplemented morphine analgesia Drug: Morphine analgesia	N/A

Detailed Description

Delirium is a state of acutely occurred and transient cerebral dysfunction. It is a common complication in elderly patients after surgery. A systematic review showed that an average of 36.8% (range 0 to 73.5%) of surgical patients developed postoperative delirium, and its occurrence increased with age. According to our previous studies, postoperative delirium developed in 51.0% of patients after cardiac surgery and in 44.5% of patients after non-cardiac surgery. The occurrence of delirium is associated with worse short-term outcomes, including increased postoperative complications, prolonged hospital stay, and increased in-hospital mortality; it is also associated with worse long-term outcomes, including declined cognitive function, decreased quality of life, and increased post-hospital mortality. Delirium is the result of multiple factors. Studies showed that postoperative pain is an important risk factor of delirium, whereas good postoperative analgesia reduces the incidence of delirium. For postoperative patients, sleep disturbances occurs frequently and increases the risk of delirium, whereas improving sleep quality reduces the incidence of delirium. Furthermore, the studies found that surgery related inflammatory response also plays an important role in the development of delirium.

Dexmedetomidine is a highly selective alpha-2 (α2) adrenoreceptor agonist that provides anxiolysis, sedation, hypnosis and analgesia. It exerts the sedative and hypnotic effects by activating the endogenous sleep pathways, and produces a condition similar to phase 2 non-rapid eye movement sleep. For patients undergoing mechanical ventilation in the ICU, dexmedetomidine sedation helps to maintain a normal circadian rhythm of sleep and improves sleep architecture. Dexmedetomidine also provides analgesic effect by activating α2 adrenergic receptors in the dorsal horn of spinal cord. When used as a supplemental drug it decreases intraoperative and postoperative requirement of opioids. Moreover, animal studies showed that dexmedetomidine significantly inhibits the degree of inflammatory response induced by endotoxin or during spinal cord injury. In clinical studies, dexmedetomidine attenuates the degree of inflammatory response following Coronary Artery Bypass Grafting surgery.

These effects of dexmedetomidine make it suitable for prevention of postoperative delirium in high-risk patients. Studies have shown that, for ICU patients requiring mechanical ventilation, sedation with dexmedetomidine reduces the incidence of delirium when compared with other sedatives; for postoperative patients, dexmedetomidine administered in combined with opioids improves analgesia and reduces opioid requirements. A recent study showed that, for elderly patients admitted to the ICU after surgery, low-dose dexmedetomidine infusion (at a rate of 0.1 ug/kg/h, for an average of 15 hours) improves analgesia for up to 24 hours, ameliorates subjective sleep quality for up to 3 days, and reduces the incidence of delirium during the first 7 postoperative days. The investigators hypothesized that the use of dexmedetomidine as a supplement to patient-controlled intravenous analgesia may also reduce the incidence of postoperative delirium.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Impact of Dexmedetomidine Supplemented Analgesia on Incidence of Delirium in Elderly Patients After Cancer Surgery: a Multicenter Randomized Controlled Trial

Actual Study Start Date :

Jan 6, 2017

Anticipated Primary Completion Date :

Apr 1, 2022

Anticipated Study Completion Date :

May 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dexmedetomidine group Dexmedetomidine supplemented morphine analgesia will be provided for patients in this group in the form of patient-controlled intravenous analgesia. The formula contains a mixture of morphine (0.5 mg/ml) and dexmedetomidine (1.25 ug/ml), diluted with normal saline to a total volume of 160 ml. 5-HT3 receptor antagonist is added when necessary. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with patient-controlled bolus of 2 ml each time and a lockout time from 6 to 8 minutes.	Drug: Dexmedetomidine supplemented morphine analgesia Patients in this group will receive patient-controlled intravenous analgesia for 3 days after surgery. The formula is a mixture of dexmedetomidine (1.25 ug/ml) and morphine (0.5 mg/ml), diluted with normal saline to 160 ml. 5-HT3 receptor antagonist is added when necessary. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with a bolus dose of 2 ml each time and a lockout time from 6 to 8 minutes according to patients' condition.
Placebo Comparator: Control group Morphine analgesia will be provided for patients in this group in the form of patient-controlled intravenous analgesia. The formula contains morphine (0.5 mg/ml), diluted with normal saline to a total volume of 160 ml. 5-HT3 receptor antagonist is added when necessary. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with patient-controlled bolus of 2 ml each time and a lockout time from 6 to 8 minutes.	Drug: Morphine analgesia Patients in this group will receive patient-controlled intravenous analgesia for 3 days after surgery. The formula is morphine (0.5 mg/ml) diluted with normal saline to 160 ml. 5-HT3 receptor antagonist is added when necessary. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with a bolus dose of 2 ml each time and a lockout time from 6 to 8 minutes according to patients' condition.

Arm

Intervention/Treatment

Experimental: Dexmedetomidine group

Dexmedetomidine supplemented morphine analgesia will be provided for patients in this group in the form of patient-controlled intravenous analgesia. The formula contains a mixture of morphine (0.5 mg/ml) and dexmedetomidine (1.25 ug/ml), diluted with normal saline to a total volume of 160 ml. 5-HT3 receptor antagonist is added when necessary. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with patient-controlled bolus of 2 ml each time and a lockout time from 6 to 8 minutes.

Drug: Dexmedetomidine supplemented morphine analgesia

Patients in this group will receive patient-controlled intravenous analgesia for 3 days after surgery. The formula is a mixture of dexmedetomidine (1.25 ug/ml) and morphine (0.5 mg/ml), diluted with normal saline to 160 ml. 5-HT3 receptor antagonist is added when necessary. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with a bolus dose of 2 ml each time and a lockout time from 6 to 8 minutes according to patients' condition.

Placebo Comparator: Control group

Morphine analgesia will be provided for patients in this group in the form of patient-controlled intravenous analgesia. The formula contains morphine (0.5 mg/ml), diluted with normal saline to a total volume of 160 ml. 5-HT3 receptor antagonist is added when necessary. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with patient-controlled bolus of 2 ml each time and a lockout time from 6 to 8 minutes.

Drug: Morphine analgesia

Patients in this group will receive patient-controlled intravenous analgesia for 3 days after surgery. The formula is morphine (0.5 mg/ml) diluted with normal saline to 160 ml. 5-HT3 receptor antagonist is added when necessary. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with a bolus dose of 2 ml each time and a lockout time from 6 to 8 minutes according to patients' condition.

Outcome Measures

Primary Outcome Measures

Incidence of delirium within 5 days after surgery [During the first 5 days after surgery]
Incidence of delirium within 5 days after surgery

Secondary Outcome Measures

Daily prevalence of delirium during the first 5 postoperative days [During the first 5 postoperative days]
Daily prevalence of delirium during the first 5 postoperative days
Length of stay in hospital after surgery [Up to 30 days after surgery]
Length of stay in hospital after surgery
Incidence of non-delirium complications after surgery [Up to 30 days after surgery]
Incidence of non-delirium complications after surgery
30-day all-cause mortality after surgery [At the time of 30 days after surgery]
30-day all-cause mortality after surgery
Quality of life in survival patients on the 30th day after surgery [On the 30th day after surgery]
Assessed with World Health Organization Quality of Life-Bref (WHOQOL-BREF)
Cognitive function in survival patients on the 30th day after surgery [On the 30th day after surgery]
Assessed with Telephone Interview for Cognitive Status-Modified (TICS-M)

Other Outcome Measures

Richmond Agitation-Sedation Scale (RASS) score during the first 5 days after surgery [During the first 5 days after surgery]
Richmond Agitation-Sedation Scale (RASS) score during the first 5 days after surgery
Cumulative morphine consumption during the first 3 days after surgery [During the first 3 days after surgery]
Cumulative morphine consumption during the first 3 days after surgery
Numeric Rating Scale (NRS) pain score during the first 5 days after surgery [During the first 5 days after surgery]
Numeric Rating Scale (NRS) pain score during the first 5 days after surgery
Numeric Rating Scale (NRS) sleep quality score during the first 5 days after surgery [During the first 5 days after surgery]
Numeric Rating Scale (NRS) sleep quality score during the first 5 days after surgery

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age >= 65 years, < 90 years;
Scheduled to undergo surgery for primary solid organ cancer under general anesthesia, with an expected duration of surgery >=2 hours;
Planned to use patient-controlled intravenous analgesia after surgery;
Provide written informed consent.

Exclusion Criteria:

Preoperative history of schizophrenia, epilepsy, parkinsonism or myasthenia gravis;
Preoperative radio- or chemotherapy;
Inability to communicate in the preoperative period because of coma, profound dementia or language barrier;
Preoperative obstructive sleep apnea (previously diagnosed as obstructive sleep apnea, or a STOP-Bang score >= 3);
Brain trauma or neurosurgery;
Preoperative left ventricular ejection fraction < 30%, sick sinus syndrome, severe sinus bradycardia (< 50 beats per minute), or second-degree or above atrioventricular block without pacemaker;
Severe hepatic dysfunction (Child-Pugh class C) or severe renal dysfunction (requirement of renal replacement therapy before surgery);
ASA classification >= IV.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Peking University First Hospital	Beijing	Beijing	China	100034
2	Peking University International Hospital	Beijing	Beijing	China	102206
3	Chongqing University Fuling Hospital	Chongqing	Chongqing	China	408099
4	Guizhou Provincial People's Hospital	Guiyang	Guizhou	China	550002
5	Affiliated Hospital of Hebei University	Baoding	Hebei	China	050031
6	The Third Xiangya Hospital of Central South University	Changsha	Hunan	China	410013
7	Zhongda Hospital Southeast University	Nanjing	Jiangsu	China	210009
8	The Second Affiliated Hospital of Air Force Medical University	Xi'an	Shaanxi	China	710038
9	Qingdao Municipal Hospital	Qingdao	Shandong	China	266011
10	Shanxi Provincial Cancer Hospital	Taiyuan	Shanxi	China	030013
11	Tianjin Hospital of ITCWM-Nankai Hospital	Tianjin	Tianjin	China	300100